Intraocular Ultrasound Doppler Techniques

ABSTRACT

Systems and methods are disclosed providing for the use of ultrasound energy to measure blood flow within blood vessels by Doppler velocity measurement. Directional high-frequency pulsed-wave Doppler measurements can be made with a suitable ultrasonic needle transducers for in vivo measuring of blood flow. A needle probe can include a ultrasonic material such as PMN-PT. Such blood flow measurements can be made in any part of the body, e.g., in the central retinal vein and branch retinal veins.

RELATED APPLICATIONS

This application is a continuation-in-part of related U.S. patentapplication Ser. No. 12/061,147 filed 2 Apr. 2008 and entitled“Preoperative and Intra-Operative Lens Hardness Measurement byUltrasound,” which claims the benefit of U.S. Provisional PatentApplication No. 60/909,496 filed 2 Apr. 2007; this application also is acontinuation-in-part of U.S. patent application Ser. No. 12/061,120filed 2 Apr. 2008 and entitled “Thrombolysis In Retinal Vessels withUltrasound,” which claims the benefit of U.S. Provisional PatentApplication No. 60/911,385 filed 12 Apr. 2007; this application claimsthe benefit of U.S. Provisional Patent Application No. 60/911,385 filed12 Apr. 2007 and U.S. Provisional Patent Application No. 61/030,075filed 20 Feb. 2008; the entire contents of all of which applications areincorporated herein by reference.

BACKGROUND

Several procedures have been devised to surgically remove theobstruction and reestablish the blood flow. During these surgeriesquantitative analysis is typically needed to evaluate blood flow.Currently, two evaluation methods are commonly used: fluoresceinangiography and ultrasound color Doppler:

Fluorescein angiography in which fundus photos are taken after injectingthe fluorescein dye into an arm vein is commonly used for bothdiagnosing retinal vein occlusion and evaluating treatments of retinalvein occlusion. Due to the medial opacities, fluorescein angiography isinadequate for both diagnosing and evaluating central retinal veinocclusion. Furthermore, in the fluorescein angiography procedure,multiple photos are taken by a camera with special filters, and they areanalyzed subjectively by ophthalmologists. This method may not besuitable for instantaneously evaluating blood flow reestablishmentduring surgeries.

Some researchers have demonstrated the feasibility of measuring theblood flow velocities from the central retinal vein and artery behindthe optic disc, using commercial color Doppler systems. These studieshave shown a significant reduction in flow velocity in the centralretinal vein in situations of central retinal vein occlusion (“CRVO”).These velocity variances may be used to diagnose CRVO. Ultrasound colorDoppler techniques have typically operated at frequencies of less than15 MHz. The corresponding achievable velocity resolutions of 1˜2 cm/sare insufficient for both the accurate clinical diagnosis and treatmentevaluation, and the bulky ultrasound probe size introduces some setupcomplexities for the instantaneous flow evaluation during surgery. Thismethod may not be suitable during an ophthalmologic surgery either.

A pulsed-wave Doppler system with a PMN-PT needle transducer has beendeveloped to measure the blood flow velocity in selected retinalvessels. See, e.g., Emanuel J. Gottlieb, et al., “PMN-PT High FrequencyUltrasonic Needle Transducers for Pulsed Wave Doppler In The Eye,” 2005IEEE Ultrasonics Symposium (IEEE 2005), the contents of which areincorporated herein by reference in their entirety.

Ultrasonic techniques have also been utilized in surgical procedures onthe eye for imaging structure and/or tissue of a surgical site. See,e.g., U.S. Pat. No. 6,676,607 to de Juan, Jr. et al., the contents ofwhich are incorporated herein by reference in their entirety.

While prior art techniques have proven useful for their respectiveintended purposes, they can present difficulties or limitations withrespect to thrombolysis in retinal eye vessels. Such drawbacks haveincluded the unwanted side effects on human tissue from high powerintensities.

SUMMARY

The present disclosures provides methods, techniques, systems, andapparatus utilizing directional high-frequency pulsed-wave Dopplermeasurements, e.g., with a suitable ultrasonic needle transducers (e.g.,one made of PMN-PT), for in vivo measuring of blood flow. Such bloodflow measurements can be made in any part of the body, e.g., in thecentral retinal vein and branch retinal veins. Suchtechniques/technology can present one or more of the followingadvantages, compared to the current evaluation methods mentioned above.

Improved velocity resolution of the measurement(s). Better velocityresolution and lower minimal detectable velocity cab be realized owingto the use of high-frequency ultrasound (e.g., >40 MHz). Such use canprovide for detection of velocities as low as 0.1 mm/s and can provide avelocity resolution of 0.005 mm/s.

Easier Use. Embodiments of the present disclosure can be easilyused/operated by ophthalmologists. A whole system can be compact, andultrasonic needle transducers and probes according to the presentdisclosure can be similar in size and shape to the microsurgicalinstruments used in an ophthalmologic surgery.

Lower cost. The total cost of systems of the present disclosure, whichcan be reusable, can be relatively low, e.g., less than $2000.

Other features and advantages of the present disclosure will beunderstood upon reading and understanding the detailed description ofexemplary embodiments, described herein, in conjunction with referenceto the drawings.

BRIEF DESCRIPTION OF DRAWINGS

Aspects of the disclosure may be more fully understood from thefollowing description when read together with the accompanying drawings,which are to be regarded as illustrative in nature, and not as limiting.The drawings are not necessarily to scale, emphasis instead being placedon the principles of the disclosure. In the drawings:

FIG. 1 depicts a design cross section of a suitable PMN-PT needletransducer for blood flow measurement, in accordance with an embodimentof the present disclosure;

FIG. 2A is a perspective view of a PMN-PT needle transducer inaccordance with an exemplary embodiment of the present disclosure; FIG.2B includes a perspective view of embodiments of needle transducers inaccordance with the present disclosure;

FIG. 3 is a box diagram representing a control system in accordance withan embodiment of the present disclosure; and

FIG. 4 depicts a method of in vivo measurement of blood flow in retinalblood vessels according to an exemplary embodiment of the presentdisclosure.

One skilled in the art will appreciate that the embodiments depicted inthe drawings are illustrative and that variations of those shown, aswell as other embodiments described herein, may be envisioned andpracticed within the scope of the present disclosure.

DETAILED DESCRIPTION

Embodiments of the present disclosure are directed to a pulsed-waveDoppler system including an ultrasonic needle transducer to measure theblood flow velocity in selected retinal vessels. The transducer caninclude a suitable active piezoelectric material. In exemplaryembodiments, a suitable piezoelectric material can include leadmagnesium niobate lead titanate (e.g., PMN-33% PT) though other suitablepiezoelectric transducer materials may be substituted or added.

Ultrasonic transducers or needle probes as disclosed herein can becombined with or coupled to various endoscopes used throughout bodycavities, e.g., as used to evaluate tumors such as melanoma, etc.Ultrasonic transducers or needle probes according to the presentdisclosure may also be combined within, coupled to, or otherwiseemployed with various suitable surgical instruments and/or components ofsurgical instruments and/or surgical systems. For example, a needleprobe (with ultrasonic transducer) can be coupled to cryogenic (cryo),laser, illumination, and/or cautery probes used for various parts of thebody, including internal body cavities. Further examples of surgicalcomponents/instruments to which needle probes can be coupled include,but are not limited to, one or more light fibers and/or opticalcoherence tomography probes, and the like.

High frequency (“HF”) ultrasound Doppler can be used to detect bloodflow in the microcirculation. In HF ultrasound applications, the largetissue attenuation at high frequency limits the penetration depth ofacoustic wave. Therefore, to facilitate blood flow measurement at atargeted or desired region of a patient's body, e.g., behind the opticdisc which is located about 2 cm away from the cornea, an HF intraoculartransducer can be inserted into the patient in an appropriate procedure.For example, to measure the blood flow behind the optic disc anultrasonic probe (also referred to as an HF transducer) can be insertedthrough the sclera or inserted around the eye (i.e., in the orbit); suchinsertion procedures can be performed in the same or a similar way asfor other microsurgical instruments used in surgery.

Exemplary embodiments of the present disclosure can include a needleprobe with a piezoelectric (e.g., PMN-PT) transducer configured at adesired angle with respect to the longitudinal axis of the probe. Forexample, exemplary embodiments with 0° and 45° tips have been fabricatedand tested successfully. In vivo studies have been carried out onrabbits. The system can measure the flow velocities from blood vessels.In exemplary embodiments, the blood vessels can be retinal vessels,including the central retinal vein and artery, and the branch retinalveins and arteries. The measurement error of this system can be lessthan 10% in exemplary embodiments.

FIG. 1 and FIG. 2 depict a PMN-PT needle transducer with diameter of 0.9mm, according to an exemplary embodiment. The embodiments depicted,e.g., transducers with 0° and 45° tips, can be used to measure bloodflow, e.g., from the central retinal vessels behind the optic disc, andblood flow from the branch retinal vessels on the retina. The PMN-PTneedle probe has the advantages of high sensitivity, affordable price,and simple fabrication procedures. The measured lateral resolution ofthe probe at 2 mm, which is the typical distance from the probe to thevessels during measurements, was about 300 μm.

FIG. 1 depicts a design cross section of a suitable PMN-PT needletransducer for retinal blood flow measurement with Doppler techniques,in accordance with an embodiment of the present disclosure.

As shown in FIG. 1, the probe 100 can include a piezoelectric material102 disposed with a needle housing 106. The piezoelectric material 102can be any suitable active piezoelectric material. One suitablepiezoelectric material is lead magnesium niobate lead titanate (e.g.,PMN-33% PT). The piezoelectric material may be attached (directly orindirectly, and with suitable electrical configuration/connection) to anelectrical connector 104 by suitable fabrication/constructiontechniques. For example, Cr/Au electrodes can be used to connect thepiezoelectric material 102 to the electrical connector 104, though otherconductive material(s) may be used. Housing 106 can be of a desireddiameter and material, e.g., steel of 1 mm diameter, which size can besuitable (or selected) for insertion into an ocular incision. The needlehousing 106 can surround a tube 108 of electrically insulating/isolatingmaterial, e.g., made of polyimide fabricated by suitable techniques. Theelectrical connector may be one suitable for connection to a controlsystem configured to control the production of acoustic energy from thetransducer, for example system 300 show and described for FIG. 3 herein.

Continuing with the description of probe 100, a conductive backingmaterial 110 can be located between the piezoelectric material 102 andthe electrical connector 104. A matching layer 112 may be located on oradjacent to the side of the probe from which acoustic energy is to beproduced. A protective coating 114 may optionally be present, withparylene being an exemplary material for the protective coating, thoughothers may be used.

FIG. 2A is a perspective view of an exemplary PMN-PT needle transducer200. FIG. 2B is an inset showing embodiments of the needle transducertip having either a 0° or 45° tip (202A, 202B) in accordance with anembodiments of a system according to the present disclosure. Otherangles may be used for the tip configuration.

For the exemplary embodiment of needle transducer 200 in FIG. 2A, a 700μm thick PMN-PT (HC Material Corp., Urbana, Ill.) was lapped to 51 μm. Amatching layer made of Insulcast 501 and Insulcure 9 (American SafetyTechnologies, Roseland, N.J.) and 2-3 μm silver particles (Sigma-AldrichInc., St. Louis, Mo.) was cured over the PMN-PT and lapped to 10 μm. Aconductive backing material, E-solder 3022 (VonRoll Isola, New Haven,Conn.), was cured over the opposite side of the PMN-PT and lapped tounder 3 mm. Active element plugs were diced out at 0.4 mm aperture (0.4mm×0.4 mm) and housed using Epotek 301 (Epoxy Technology Inc.,Billerica, Mass.) within a polyimide tube with inner diameter of 0.57 mm(MedSource Technologies, Trenton, Ga.). An electrical connector wasfixed to the conductive backing using a conductive epoxy. The polyimidetube provided electrical isolation from the 20 gage needle housing withinner diameter 0.66 mm. An electrode was sputtered across the silvermatching layer and the needle housing to form the ground planeconnection. Vapor deposited parylene with thickness of 13 μm was used tocoat the aperture and the needle housing.

As described previously, a suitable electronic system can be used tocontrol/excite a needle probe (e.g., probe 200 of FIG. 2A) used forultrasound-based thrombolysis according to the present disclosure. Anexample of such a system is shown in FIG. 3.

FIG. 3 is a box diagram representing an exemplary system 300 (orcontroller) for controlling a needle probe (e.g., a PMN-PT needle probedescribed for FIGS. 1-2), in accordance with an embodiment of thepresent disclosure. System 300 can include both (i) excitationcomponents for controlling the ultrasonic output of a transducer, e.g.,needle probes 100 and 200 of FIGS. 1-2, and also (ii) optionalcircuitry/components for Doppler detection of blood flow in retinalblood vessels.

As shown in FIG. 3, system 300 can include a piezoelectric transducer orprobe 302. Probe 302 can be connected to, or operation to receivesignals/pulses from a pulse generation block, which can include a poweramplifier 306, timing circuitry 310, and a suitable clock or oscillator312, e.g., a 45 MHz clock generator (or oscillator). System 300 canoperate as a pulser, e.g., a N-cycle bipolar pulser, to generate one ormore suitable pulses for supplying the transducer 302 with electricalenergy for conversion to acoustic ultrasound energy. In exemplaryembodiments, system 300 can produce a N-cycle bi-polar pulse with 70Vpp, for the control of the associated ultrasonic probe/transducer 302.The pulse repetition frequency (PRF) of the produced pulse(s) producedby system 300 can be adjusted as desired, e.g., from 100 Hz to 100 KHz,and the cycle count of the pulse can be adjusted as desired, e.g., from1 to 255. Both the PRF and cycle count can correspond to differentacoustic intensities, e.g., different flow velocities created by theacoustic streaming or the actual measured velocities.

In exemplary embodiments, the system 300 can include a clock generatoroperating at a desired frequency, e.g., 45-46 MHz, timing circuits, anda N-cycle bipolar pulser. Using the system, a N-cycle bi-polar pulsewith 20˜70Vpp can be generated. The pulse repetition frequency (PRF) ofpulse can be adjusted from 100 Hz to 100 KHz, and the cycle count of thepulse can be adjusted from 1 to 255. The pulses can be used to excitethe transducers. The received echoes from the needle transducer arepreferably limited and then amplified, e.g., by Miteq-1114. Theamplified signals can be first band-pass filtered by a 45 MHz customband-pass filter and then fed to the in-phase and quadraturedemodulator. The demodulated intermediate frequency (IF) signals can below-pass filtered to remove harmonics and noise by low-pass filters.Then the signals can be sampled and held. Followed by the PRF filters,the sampled-and-held signals can be cleaned by removing sample-and-holdharmonics. Also the optional wall filters can be followed to removelow-frequency clutter signals. Finally, the amplified Doppler signalscan be played by the stereo speakers and digitized by a sound card. Thedigitized Doppler signals can be converted into a directionalspectrogram, e.g., by Labview software in real time. Further off-lineanalysis can be conducted, e.g., using MatLab based software. In anexemplary embodiment, a micro flow phantom consisting of 127˜574 μmtubes was set up and was used to evaluate the system.

FIG. 4 depicts a method 400 of measuring blood flow in a blood vesselaccording to an exemplary embodiment of the present disclosure. Theblood vessels can be anywhere in a patient's body, e.g., the eye, heart,leg, etc. An ultrasound transducer can be inserted into a patient, asdescribed at 402. The transducer may be place over targeted bloodvessels, as described at 404. The targeted blood vessels may include oneor more blood clots. Ultrasonic energy can be produced from thetransducer of a probe, e.g., probe 200A of FIG. 2B, as described at 406.For example, an electronic control system according (or similar) to FIG.3 can be used to control the production, e.g., 406, or ultrasonicenergy.

Continuing with the description of method 400, the ultrasonic energy canbe directed to the targeted, e.g., retinal, vessels, as described at408. Directing ultrasonic energy can include producing acousticstreaming in the blood of the targeted blood vessels. As described at410, measurement of blood flow (e.g., velocity and/or flow rate) in thetargeted blood vessels can accordingly be effected.

Accordingly, compared to the existing technologies, embodiments of thepresent disclosure can provide the advantage of better velocityresolution and lower minimal detectable velocity. Because we are usingthe high-frequency ultrasound (>45 MHz), the proposed method can detectvelocities as low as 0.1 mm/s and has a velocity resolution of 0.005mm/s. Techniques and apparatus of the present disclosure can be mucheasier to use than prior art techniques. Systems according to thepresent disclosure can be compact and needle probes with a piezoelectric(e.g., PMN-PT) transducer can be similar in size and shape to themicrosurgical instruments used in an ophthalmologic surgery. Systems ofthe present disclosure, which can be disposable, can be relativelyinexpensive.

Moreover, a needle probe according to the present disclosure, such asdepicted in FIGS. 1-2, can provide the advantages of high efficiency,affordable price, and simple fabrication procedures. Such a probe canhave a (natural) focal point at a desired distance from the tip of theprove, e.g., at approximately 1˜2 mm. For an exemplary embodiment, aPMN-NT probe according to FIGS. 1-2 had a measured lateral resolution ofabout 300 μm at a distance of 2 mm. Such lateral resolution and focaldistance parameters can be particularly useful for clot dislodging as atypical central retinal vein locates at 1 mm below the optical nerve.

While certain embodiments have been described herein, it will beunderstood by one skilled in the art that the methods, systems, andapparatus of the present disclosure may be embodied in other specificforms without departing from the spirit thereof. For example, whilecertain piezoelectric materials have been mentioned specifically, othersmay be used within the scope of the present disclosure.

Accordingly, the embodiments described herein are to be considered inall respects as illustrative of the present disclosure and notrestrictive.

1. A system comprising: an ultrasound probe including an ultrasonictransducer for producing an output of ultrasound energy, the probe beingconfigured and arranged for insertion in a patient; a control unitconnected to the ultrasound transducer and configured and arranged tocontrol the production of ultrasound energy from the transducer; and ameasurement unit configured and arranged to measure blood flow withinblood vessels by Doppler velocity measurement.
 2. The system of claim 1,wherein the ultrasound transducer comprises a flat, angled or beveledtip.
 3. The system of claim 1, wherein the ultrasonic transducercomprises a piezoelectric material.
 4. The system of claim 3, whereinthe piezoelectric material comprises PMN-PT.
 5. The system of claim 1,wherein the ultrasound transducer includes a cylindrical housing.
 6. Thesystem of claim 5, wherein the cylindrical housing comprises steel. 7.The system of claim 6, wherein the steel comprises stainless steel. 8.The system of claim 5, further comprising a flexible tube disposedwithin the cylindrical housing.
 9. The system of claim 8, wherein theflexible tube comprises polyimide.
 10. The system of claim 4, whereinthe PMN-PT comprises PMN-33% PT.
 11. The system of claim 1, wherein thecontrol unit comprises timing circuitry and a power amplifier.
 12. Thesystem of claim 1, wherein the control unit is configured and arrangedto control the intensity of the output.
 13. The system of claim 1,wherein the control unit is configured and arranged to control the pulserepetition frequency (PRF) of the output.
 17. The system of claim 1,wherein the transducer and controller are configured and arranged toproduce ultrasonic energy at a frequency of about 1 MHz to about 50 MHz.18. The system of claim 1, wherein the controller is configured andarranged to produce a pulse repetition frequency of about 100 Hz toabout 100 kHz.
 19. The system of claim 1, wherein the controller isconfigured ad arranged to produce a pulse cycle count from 1 to
 255. 20.A method of measuring blood flow in a blood vessel, the methodcomprising: inserting a needle probe with an ultrasonic transducer intoa patient; placing the transducer over blood vessels and/or tissue in apatient's body; producing ultrasonic energy from the transducer;directing the ultrasonic energy to the blood vessels; and measuringblood flow within blood vessels by Doppler velocity measurement.
 21. Themethod of claim 20, wherein measuring blood flow within blood vesselsincludes measuring blood velocity.
 22. The method of claim 20, furthercomprising measuring volumetric flow rate.
 23. The method of claim 20,further comprising coupling the needle probe to a surgical instrument orcomponent.
 24. The method of claim 23, wherein the surgical instrumentor component comprises an endoscope, a laser probe, a cryoprobe, a lightfiber, and/or an optical coherence tomography probe.
 25. The method ofclaim 20, further comprising receiving ultrasonic energy reflected fromthe targeted blood vessels.
 26. The method of claim 20, wherein theultrasonic transducer comprises PMN-PT.
 27. The method of claim 20,wherein producing ultrasonic energy from the transducer comprisesproducing ultrasonic energy at a frequency of about 1 MHz to about 50MHz.
 28. The method of claim 20, wherein the ultrasonic energy isproduced at a frequency of about 44 MHz to about 24 MHz.
 29. The methodof claim 20, wherein producing ultrasonic energy from the transducercomprises producing a pulse repetition frequency of about 100 Hz toabout 100 kHz.
 30. The method of claim 20, wherein producing ultrasonicenergy from the transducer comprises producing a pulse cycle count from1 to
 255. 31. The method of claim 20, wherein producing ultrasonicenergy from the transducer comprises using a piezoelectric needle probe.32. The method of claim 20, wherein inserting the needle probe into apatient comprises inserting the needle probe into the patient's eye. 33.The method of claim 32, wherein placing the transducer over bloodvessels and/or tissue in a patient's body comprises placing thetransducer over or adjacent to retinal vessels of the eye or the opticnerve of the patient.